Background/Purpose: In the pathogenic mechanisms of antiphospholipid syndrome (APS), it is recognized that pathogenicity of antiphospholipid antibodies (aPL) has dominant effects. Complement is the part of the innate immune system and is one of the main effector mechanisms of antibody-mediated immunity. We have previously reported that complement activation prevalently coexists in sera of antiphospholipid syndrome (APS) patients and functions as source of procoagulant cells activation. Recently, autoantibodies against C1q, the component of complement 1, were reported to correlate with complement activation in patients with systemic lupus erythematosus (SLE). They are not neutralizing antibodies but target the neoepitopes of deformed C1q bound to various molecules such as anionic phospholipids. The binding of anti-C1q antibodies to C1q induces accelerated activation of complement pathway. There are no previous studies discussing the involvement of anti-C1q antibodies in APS patients. The purpose of this study is to investigate the existence and significance of anti-C1q antibodies in APS patients. Methods:  This study was comprised of 40 consecutive primary APS patients that visited Hokkaido University Hospital rheumatology clinic from 2002 to 2013 that had more than 2 years history of APS. Informed consent was obtained from every patients and the study was approved by ethics committee of the Hokkaido University Hospital. All the patients were retrospectively analyzed of their clinical manifestations and laboratory data. Ten patients had refractory APS defined as a clinical status of relapsing thrombosis or pregnancy morbidity during adequate secondary prophylaxis.  Twenty non-SLE connective tissue disease patients without APS and 20 healthy control subjects were also included. An enzyme-linked immunosorbent assays (ELISA) were used to measure serum levels of anti-C1q antibody titers and anaphylatoxins (C3a,C4a). Results: Anti-C1q antibodies were more frequently detected in primary APS patients (14/40) than in non-SLE connective tissue disease patients (2/20) (p<0.01). In APS patients, anti-C1q antibodies titers were significantly correlated with serum C4a levels (p=0.013) and showed tendency of inverse correlation with serum C3a levels (p=0.07).  The prevalence or the titers of anti-C1q antibodies were not associated with any of the specific clinical manifestations of APS or titers of aPLs. However, refractory APS patients, compared with APS patients without flare, had higher positivity (9/10 vs 3/20, p=0.01) and higher titers of anti-C1q antibodies( 32.9+/- 6.95 vs 10.9+/-1.89, p=0.01). Using a cut-off level of 20, the hazard ratio of the anti-C1q positivity for the reoccurrences of the APS manifestation during adequate secondary prophylaxis were 80.0 (95%CI 7.45-880, p=0.000007). Conclusion: These findings indicate that anti-C1q antibodies are associated with complement activation in APS and may contribute to the manifestation especially in the refractory cases.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoantibodies-against-component-of-complement-one-contribute-to-the-complement-activation-and-clinical-manifestation-of-antiphospholipid-syndrome-aps-especially-in-refractory-cases/